Abstract

Glioblastomas (GBM) are the most aggressive and prevalent form of gliomas with abysmal prognosis and limited treatment options. We analyzed clinically relevant molecular aberrations suggestive of response to therapies in 1035 GBM tumors. Our analysis revealed mutations in 39 genes of 48 tested. IHC revealed expression of PD-L1 in 19% and PD-1 in 46%. MGMT-methylation was seen in 43%, EGFRvIII in 19% and 1p19q co-deletion in 2%. TP53 mutation was associated with concurrent mutations, while IDH1 mutation was associated with MGMT-methylation and TP53 mutation and was mutually exclusive of EGFRvIII mutation. Distinct biomarker profiles were seen in GBM compared with WHO grade III astrocytoma, suggesting different biology and potentially different treatment approaches. Analysis of 17 metachronous paired tumors showed frequent biomarker changes, including MGMT-methylation and EGFR aberrations, indicating the need for a re-biopsy for tumor profiling to direct subsequent therapy. MGMT-methylation, PR and TOPO1 appeared as significant prognostic markers in sub-cohorts of GBM defined by age. The current study represents the largest biomarker study on clinical GBM tumors using multiple technologies to detect gene mutation, amplification, protein expression and promoter methylation. These data will inform planning for future personalized biomarker-based clinical trials and identifying effective treatments based on tumor biomarkers.

Numbers in parentheses represent the N number of each subgroup. Data analysis was done on the GBM cohort (N=1035); a comparison with grade III astrocytoma (N=107) was also performed. Numbers next to test platforms represent number of tumors with results from each platform. The tests done and test platform used on each tumor are variable, the details of which are shown in Table .

Shown are biomarkers that are statistically different in GBM and grade III astrocytomas by two-tailed Fisher-Exact test. Asterisks indicate comparisons that remain statically significant after correcting for multiple comparisons by Bonferroni correction. Numbers on the bar indicates positive N/total N for each biomarker tested.

Primary/Recurrence: R, paired recurrent tumors; P: paired primary and recurrent tumors; U: unknown. Yellow: biomarkers that decreased over time, which included loss of protein overexpression by IHC; loss of gene amplification by ISH and loss of gene mutation by sequencing; loss of MGMT promoter methylation by pyrosequencing. Blue: biomarkers that increased over time, which included acquisition of protein expression by IHC, acquisition of gene amplification by ISH; acquisition of gene mutation by sequencing; acquisition of MGMT promoter methylation by pyrosequencing. Gray: no biomarker change over time.